This is the second and final submission of the competitive renewal of R01 MH077139, A Large-Scale Schizophrenia Association Study in Sweden. This project has been very successful with all aims accomplished and, indeed, exceeded. We successfully ascertained the numbers of cases and controls for which we were funded (N~12,996 in total). Instead of candidate gene genotyping, we conducted GWAS on around half the sample. These data were key components in two International Schizophrenia Consortium Nature papers and are a sizable fraction of the Psychiatric GWAS Consortium schizophrenia mega-analysis. Finally, our Swedish sample is being used for two """"""""grand opportunity"""""""" NIH grants (exome sequencing and genome-wide methylomics). We propose here new aims that use this unique sample to increase our knowledge of SCZ and to keep this highly productive team intact. The samples studied here will increase available samples for SCZ by 61% which will provide substantially enhanced power for detection of networks and loci that confer risk or protection.
In Aim 1, we will complete the genomic characterization of the full sample of 12,996 subjects (5,851 SCZ cases, 7,145 controls). This includes GWAS genotyping and a novel Illumina """"""""exome chip"""""""" on all subjects plus exome sequencing on 1,000 cases and 1,000 controls. All assays are funded by philanthropy. We request funds for our team to conduct rigorous quality control, imputation, and data warehousing.
In Aim 2, we will conduct analyses designed to elucidate genetic effects that confer risk or protection for SCZ. ? (2a) Pathway and network analyses: identify additional high-confidence pathways for SCZ by rigorous assessment of whether genomic results are enriched for smaller p-values in genes in classical and novel empirical pathways. ? (2b) Conduct the first highly powered genome-scale analysis of exome polymorphism in SCZ. The novel exome chip was developed by Illumina and our colleagues at the Broad, and captures missense and nonsense coding variation with MAF e0.1%, and a substantial fraction with MAF 0.01-0.1%. This could identify low-frequency missense or nonsense polymorphisms that contribute to SCZ. (2c) Analyze directly genotyped and imputed common variants in the Swedish data, and meta-analyze with the PGC SCZ results. Conduct verification genotyping as required. Anticipated outcome: genome-wide significant evidence for 10-20 novel loci. (2d) Identify structural variation contributing to SCZ. Conduct the first systematic evaluations of CNPs, indels, novel insertions, and other structural polymorphisms. Evaluate CNV associations with SCZ, and meta-analyze with external results. Conduct verification genotyping as required. Anticipated outcome: increase understanding of the major CNV loci, and the role of novel structural variants.
In Aim 3, estimate if high-confidence genetic effects are modified by established epidemiological risk factors for SCZ. For this complex trait, environmental risks may generally interact with causal genetic variation.
For Aim 2 results, are genetic effects strengthened or lessened if epidemiological risk factors are modeled? Risk factors are from high-quality databases and were often assessed prospectively (season of birth, urban/rural birth, paternal and grandparental age, pre-morbid cognitive attainment, and head trauma). Anticipated outcome: understanding of how specific genetic and environmental risk factors interact in SCZ that could lead to new mechanistic hypotheses. Our goal is rapidly to learn more about the genetics of schizophrenia and how genes and environment might act and interact to alter disease risk. We propose to do this using the largest and most comprehensively studied sample collection in the field and which includes both genetic and environmental risk factors.

Public Health Relevance

Schizophrenia causes enormous human suffering and cost to society. Our goal is rapidly to learn more about the genetics of schizophrenia and how genes and environment might act and interact to alter disease risk. We propose to do this using the largest and most comprehensively studied sample collection in the field and which includes both genetic and environmental risk factors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH095034-03
Application #
8727098
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Addington, Anjene M
Project Start
2012-08-15
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Marshall, Christian R (see original citation for additional authors) (2017) Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet 49:27-35
Visscher, Peter M; Wray, Naomi R; Zhang, Qian et al. (2017) 10 Years of GWAS Discovery: Biology, Function, and Translation. Am J Hum Genet 101:5-22
Singh, Tarjinder; Walters, James T R; Johnstone, Mandy et al. (2017) The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nat Genet 49:1167-1173
Nguyen, Hoang T; Bryois, Julien; Kim, April et al. (2017) Integrated Bayesian analysis of rare exonic variants to identify risk genes for schizophrenia and neurodevelopmental disorders. Genome Med 9:114
Leonenko, Ganna; Richards, Alexander L; Walters, James T et al. (2017) Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 174:724-731
Direk, Nese; Williams, Stephanie; Smith, Jennifer A et al. (2017) An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype. Biol Psychiatry 82:322-329
Franke, Barbara; Stein, Jason L; Ripke, Stephan et al. (2016) Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept. Nat Neurosci 19:420-431
Minikel, Eric Vallabh; Vallabh, Sonia M; Lek, Monkol et al. (2016) Quantifying prion disease penetrance using large population control cohorts. Sci Transl Med 8:322ra9
Fromer, Menachem; Roussos, Panos; Sieberts, Solveig K et al. (2016) Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci 19:1442-1453
Genovese, Giulio; Fromer, Menachem; Stahl, Eli A et al. (2016) Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat Neurosci 19:1433-1441

Showing the most recent 10 out of 29 publications